Project Summary/Abstract Hepatitis C virus (HCV) and human pegivirus (GB virus C) are globally distributed and infect 2- 5% of the human population. The lack of tractable animal models for these viruses, in particular for HCV, has hampered the study of infection, transmission, virulence, immunity and pathogenesis. To address this challenge, we searched for their virus homologs in small mammals, including wild rodents. Results of our ongoing studies identify, for the first time, several new species of hepaciviruses (HCV-like viruses) and pegiviruses (GBV-like viruses) in wild rodents. The presence of genes, encoded proteins and translation elements homologous to those found in human viruses, lead us to hypothesize that these different rodent virus species resemble HCV or GBV-C in their biological properties. The proposed genetic and biological characterization of these novel rodent viruses will enable the development of tractable animal models with which to study virus-host interactions and may culminate in new strategies for therapeutic intervention. We propose two specific aims: Aim-1: Identify rodent HCV and GBV-C like viruses (HGLVs) and characterize their complete genomes, natural host and species tropism; and Aim-2: Investigate HGLV infection, tissue tropism and pathogenesis using experimental infections of natural host animal species. Pursuit of these aims will lead to identification of the new rodent HGLV species that are similar to their human homologs in tissue tropism and pathogenesis. Results of our studies will open up new avenues of research on HCV and GBV-C like viruses, and will help in identifying virus and host factors that determine hepacivirus and pegivirus tissue and species tropism, persistence, virulence, immune escape and pathogenesis.